Gene Therapy for Treating Depression

For decades, medications for depression have acted pretty much the same way–by manipulating levels of serotonin and other chemical messengers in the brain. New drugs have offered only modest changes from the old ones.

Now a team of researchers, led by Michael Kaplitt, an associate professor at Weill Cornell Medical College, has proposed a different way to attack depression: by using gene therapy to boost levels of a protein called p11 in an area of the brain called the nucleus accumbens.

“We do believe that the deficiency of this gene in this area of the brain may be one of the underlying root causes of depression, and that addressing that could help improve symptoms,” says Kaplitt.

The gene responsible for normal levels of p11 has previously been linked to clinical depression. Kaplitt’s new study, published in the current issue of the journal Science Translational Medicine, show that altering levels of this protein in the nucleus accumbens via gene therapy can ameliorate symptoms of depression in mice. A second experiment described in the same paper shows that people diagnosed with depression have lower levels of the protein in this part of the brain.

Roughly 2 to 3 percent of males and 6 to 7 percent of females have severe depression. For about 40 percent of these people, current medications don’t fully resolve their symptoms, according to Schahram Akbarian, a psychiatrist and molecular neuroscientist at the University of Massachusetts Medical School. Akbarian was not involved with the new research. Most medications for depression are based on ideas that are now 50 to 60 years old, he says, and the field desperately needs new targets for drug development.

Dozens of genes have been linked to depression in animal models, and major depression in people does run in families, suggesting a genetic component, as well as an environmental one. Previous studies have identified dysfunction of genes involved in serotonin signaling, such as p11, as among the culprits in depression.

Kaplitt and his team focused their research on the nucleus accumbens, which is involved in sensing satisfaction, reward, and pleasure. There is increasing evidence, he says, that this area is dysfunctional in patients with depression.

The researchers found that when they blocked p11 function in their nucleus accumbens in normal mice, the mice showed signs of depression. They drank less sugar water than their healthy counterparts and struggled less when held by the tail, two standards tests of depression in mice. This adds to previous evidence suggesting that p11 in this brain area plays a crucial role in depression. (Depressed mice seem to get less pleasure from this mouse “candy” and quickly give up the fight when they are held by the tail, according to standard research protocol.)